NADPH Oxidase 1, a Novel Molecular Source of ROS in Hippocampal Neuronal Death in Vascular Dementia

Abstract

Aims: Chronic cerebral hypoperfusion (CCH) is a common pathological factor that contributes to neurodegenerative diseases such as vascular dementia (VaD). Although oxidative stress has been strongly implicated in the pathogenesis of VaD, the molecular mechanism underlying the selective vulnerability of hippocampal neurons to oxidative damage remains unknown. We assessed whether the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) complex, a specialized superoxide generation system, plays a role in VaD by permanent ligation of bilateral common carotid arteries in rats. Results: Male Wistar rats (10 weeks of age) were subjected to bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]). Nox1 expression gradually increased in hippocampal neurons, starting at 1 week after 2VO and for approximately 15 weeks after 2VO. The levels of superoxide, DNA oxidation, and neuronal death in the CA1 subfield of the hippocampus, as well as consequential cognitive impairment, were increased in 2VO rats. Both inhibition of Nox by apocynin, a putative Nox inhibitor, and adeno-associated virus-mediated Nox1 knockdown significantly reduced 2VO-induced reactive oxygen species generation, oxidative DNA damage, hippocampal neuronal degeneration, and cognitive impairment. Innovation and Conclusion: We provided evidence that neuronal Nox1 is activated in the hippocampus under CCH, causing oxidative stress and consequential hippocampal neuronal death and cognitive impairment. This evidence implies that Nox1-mediated oxidative stress plays an important role in neuronal cell death and cognitive dysfunction in VaD. Nox1 may serve as a potential therapeutic target for VaD. Antioxid. Redox Signal. 21, 533-550.

NADPH oxidase in brain injury and neurodegenerative disorders

“…Another study showed that NOX1 and NOX3 mRNA levels are increased in the brain during early stages of AD [201]. Interestingly, NOX1 mRNA levels were also reported to be significantly elevated in the hippocampal CA1 region in a bilateral cerebral artery occlusion (BCCAO) rodent model of vascular dementia, and the effect correlated with increased superoxide and ROS levels [202]. As a whole, these studies provide correlational evidence of increased NADPH oxidase subunit expression and NADPH oxidase activity in the brain in AD, which could contribute to AD pathology.…”

Acupuncture inhibits TXNIP‐associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats

“…Overproduction of reactive species oxygen (ROS) and inflammation resulting from ischemia are two major contributors to the pathogenesis of VD . During CCH, endogenous antioxidants decrease, along with an increase in oxidative damage to protein, lipid, and DNA .…”

“…4 Overproduction of reactive species oxygen (ROS) and inflammation resulting from ischemia are two major contributors to the pathogenesis of VD. 5,6 During CCH, endogenous antioxidants decrease, along with an increase in oxidative damage to protein, lipid, and DNA. 7 As an intracellular endogenous regulator of oxidative stress and inflammation, thioredoxin-interacting protein (TXNIP) played a critical part in ischemic diseases in many studies.…”

Inhibiting NADPH oxidase protects against long-term memory impairment induced by neonatal sevoflurane exposure in mice

“…11 12 Indeed, previous studies have shown that superoxide production by NADPH oxidase underlies cognitive impairment after cerebral ischaemia and traumatic brain injury. [13][14][15] However, the role of NADPH oxidase in memory impairment has not been examined in animals exposed to anaesthesia in the neonatal period. Furthermore, it is not known whether targeting NADPH oxidase during anaesthesia protects the neonatal brain from long-term memory deficits.…”